Two forms of cyclooxygenases are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The therapeutic use of conventional COX inhibitors are limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A number of selective COX-2 inhibitors have been described which are anti-inflammatory in a variety of animal models but which, unlike non-selective COX inhibitors, do not produce gastrointestinal pathology. See, for example, U.S. Pat. Nos. 5,380,738; 5,344,991; 5,434,178; 5,466,823; 5,474,995; 5,510,368; 5,521,207; 5,604,260; and 6,048,850, all of which are incorporated herein by reference.
Kadin, U.S. Pat. No. 4,569,942 (“Kadin”), incorporated herein by reference, discloses a broad class of N,3-disubstituted 2-oxindole-1-carboxamide compounds that are generically referred to as inhibitors of cyclooxygenase and lipoxygenase, and that are said to be useful as analgesic and antiinflammatory agents in mammalian subjects, particularly man. Kadin, however, does not mention inhibition of COX-2 and, therefore, does not identify or suggest which compounds within the broad disclosure might have a particular utility for inhibiting COX-2, much less in animals other than humans.